LAMP2A gene therapy mitigates Parkinson’s disease–related pathology in nonhuman primates
Chaperone-mediated autophagy (CMA), regulated by its lysosomal receptor LAMP2A, is a key pathway for αSynuclein (αSyn) clearance and a direct target of αSyn-related neurotoxicity. Rodent studies show that LAMP2A enhancement reverses neurodegeneration, whereas its deficiency accelerates pathology. To test translational relevance, we examined whether increasing LAMP2A expression in nonhuman primates could mitigate α-synucleinopathy induced by injections of Parkinson's disease patient-derived Lewy body (LB) extract. Increasing LAMP2A expression protected nigral dopaminergic neurons from LB-induced αSyn neurodegeneration, delayed the formation and release of pathology-related αSyn species, and evoked a beneficial effect on motor behavior and on cognitive functions of the primate model. Our findings provide preliminary preclinical evidence supporting CMA enhancement as a therapeutic strategy for αSynucleinopathies.
Authors
- Benjamin Dehay (ORCID: https://orcid.org/0000-0003-1723-9045)
- Erwan Bézard (ORCID: https://orcid.org/0000-0002-0410-4638)
- Maria Xilouri (ORCID: https://orcid.org/0000-0001-7038-0780)
- Marie-Laure Arotçarena (ORCID: https://orcid.org/0000-0002-1306-3700)
- Morgane Darricau (ORCID: https://orcid.org/0000-0002-6663-3156)
- Mélyna Achour
- Rémy Steinschneider
- Nanna Møller Jensen (ORCID: https://orcid.org/0000-0003-1177-5197)
- Nathalie Dutheil (ORCID: https://orcid.org/0000-0001-9121-217X)
- Poul Henning Jensen (ORCID: https://orcid.org/0000-0002-4439-9020)
- Sandra Doveró (ORCID: https://orcid.org/0000-0002-5781-1328)
- Karim Harhouri (ORCID: https://orcid.org/0000-0003-2904-5221)
- Vincent Planche (ORCID: https://orcid.org/0000-0003-3713-227X)
- Deniz Kirik (ORCID: https://orcid.org/0000-0002-1360-1265)
- Elsa Y. Pioli
- Leonidas Stefanis (ORCID: https://orcid.org/0000-0003-3569-8990)
- Maria Fouka
- Marie-Laure Thiolat (ORCID: https://orcid.org/0000-0003-2586-756X)
- Emilie Noe (ORCID: https://orcid.org/0009-0002-8846-2148)
- Qin Li (ORCID: https://orcid.org/0009-0004-3560-4469)
- Anna Lovisotto
- Elena Georgia Gialinaki
- Hugo Jadot (ORCID: https://orcid.org/0009-0008-9979-4125)
- Marianna Giannopoulou
- Elio Balpe
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université de Bordeaux (FR)
- Lund University (SE)
- National and Kapodistrian University of Athens (GR)
- Aarhus University (DK)
- Institut des Maladies Neurodégénératives (FR)
- Biomedical Research Foundation of the Academy of Athens (GR)
- Institut Interdisciplinaire de Neuroscience (FR)
- Motac Neuroscience (United Kingdom) (GB)
- Génétique et biologie du développement (FR)
- Laboratoire Physiopathologie et Génétique du Neurone et du Muscle (FR)
Publication Details
- Journal
- Science Advances
- Published
- 2026-10-30
- DOI
- https://doi.org/10.1126/sciadv.aeg1787
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Michael J. Fox Foundation for Parkinson's Research
- Parkinson's Disease Foundation
- Fondation pour la Recherche Médicale
- Lundbeckfonden
- Université de Bordeaux
- Foundation for Research and Technology-Hellas